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Alpha-Lipoic Acid
Monograph
α - Lipoic Acid
S
S
CH2
CH2
CH2
CH2
CH2
CH2
COOH
CH2
Dihydrolipoic Acid
SH
SH
CH2
CH2
CH2
Alpha-lipoic Acid
CH2
Introduction
Alpha-lipoic acid (ALA – also known as
thioctic acid) was discovered in 1951 as a molecule that assists in acyl-group transfer and as a
coenzyme in the Krebs cycle. In the 1980s, the
scientific community realized alpha-lipoic acid is
a powerful antioxidant. Several qualities distinguish alpha-lipoic acid from other antioxidants: ALA can be synthesized by animals and humans;1 it neutralizes free radicals in both the fatty and watery regions of cells, in contrast
to vitamin C (water soluble) and vitamin E (fat soluble); and, ALA functions as an antioxidant in both its reduced
and oxidized forms.2
CH2
CH2
CH2
COOH
Pharmacokinetics
ALA appears to be readily absorbed from an oral dose and converts easily to its reduced form, dihydrolipoic acid (DHLA), in many tissues of the body.3 The effects of ALA and DHLA are present both intra- and extracellularly.
ALA contains an asymmetrical carbon and thus has two possible optical isomers. These are designated as
R-lipoic acid (R-ALA) and S-lipoic acid (S-ALA). Naturally occurring ALA is in the R configuration, bound to a
protein where it functions as an essential cofactor for several mitochondrial enzyme complexes involved in energy
production and the catabolism of alpha-keto acids and amino acids.4
Nutritional supplements of ALA are typically comprised either of R-ALA alone or a racemic mixture of
R-ALA and S-ALA (RS-ALA). Human studies using oral racemic mixtures of ALA have observed plasma concentrations of R-ALA to be greater than that of S-ALA.5,6 One study found that, following oral administration of 50- or
600-mg racemic mixture of lipoic acid, maximum plasma concentrations (Cmax) of R-ALA were double that of
S-ALA (following 50-mg dose: 135.45 ng/mL and 67.83 ng/mL, respectively; following 600-mg dose: 1,812.32
ng/mL and 978.20 ng/mL, respectively).6
Mechanisms of Action
Alpha-lipoic acid is a potent antioxidant in both fat- and water-soluble mediums. Furthermore, its antioxidant activity extends to both its oxidized and reduced forms. DHLA is capable of directly regenerating ascorbic
acid from dehydroascorbic acid and indirectly regenerating vitamin E.7 Researchers have also found ALA increases
intracellular glutathione8 and coenzyme Q109 levels.
Alpha-lipoic acid appears capable of chelating certain metals. It forms stable complexes with copper, manganese, and zinc.10 In animal studies, it has been found to protect against arsenic poisoning,11 and, in both animal
and in vitro studies, ALA reduced cadmium-induced hepatotoxicity.12 In vitro, ALA chelated mercury from renal
slices.13
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Alpha-Lipoic Acid
Monograph
Mechanisms that may account for lipoic
acid’s benefit in preventing diabetic complications
include prevention of protein glycosylation14 and inhibition of the enzyme aldose reductase, the latter of
which subsequently inhibits conversion of glucose
and galactose to sorbitol.15,16 Accumulation of sorbitol has been implicated in the pathogenesis of various
diabetic complications, including “sugar cataracts”
where sorbitol accumulates in the lens.
Clinical Indications
Diabetes
Lipoic acid has the potential to prevent diabetes (at least in animals), influence glucose control,
and prevent chronic hyperglycemia-associated complications such as neuropathy.
Blood-sugar Management/Insulin Sensitivity
Acting as a potent antioxidant, DHLA protected rat pancreatic islet cells from destruction by
reactive oxygen species.17 In vitro, lipoic acid stimulated glucose uptake by muscle cells in a manner
similar to insulin.18
Type 2 diabetics given 1,000 mg lipoic acid
intravenously (IV) experienced a 50-percent improvement in insulin-stimulated glucose uptake.19 In
an uncontrolled pilot study, 20 type 2 diabetics were
given 500 mg lipoic acid IV for 10 days. While there
was an average 30-percent increased uptake of glucose, there were no changes in fasting blood sugar or
insulin levels.20
In a study examining the effect of lipoic acid
as a co-factor of the pyruvate dehydrogenase complex on both lean and obese type 2 diabetics, insulin
sensitivity, glucose effectiveness, serum lactate levels, and pyruvate levels were tested after oral glucose
tolerance load. Treatment with 600 mg ALA twice
daily for four weeks increased insulin sensitivity and
prevented serum lactate/pyruvate-induced hyperglycemia.21
In a placebo-controlled, multi-center pilot
study, 74 patients with type 2 diabetes were randomized to receive 600 mg ALA or placebo orally once,
twice, or three times daily, for four weeks. Although
no significant differences regarding the various doses
of ALA were observed, at the end of the trial it was
found that patients who received ALA experienced
significant improvement in insulin-stimulated glucose disposal compared to those on placebo (+27%;
p<0.01). This suggests oral administration of ALA
can improve insulin sensitivity in type 2 diabetics.22
Experimental research indicates R-ALA may
be more effective than S-ALA in improving insulin
sensitivity. In an animal model of non-diabetic insulin resistance, R-ALA for 10 days increased glucose
uptake by skeletal muscle of obese rats by 65 percent,
compared to 29 percent with S-ALA. In addition, RALA significantly reduced plasma insulin by 17 percent; whereas, S-ALA increased insulin levels by 15
percent. This seems to indicate an increase in insulin
resistance with S-ALA.23
Diabetic Nephropathy
One animal study suggested that ALA may
be effective in the prevention of early diabetic glomerular injury and may provide more protection than
high doses of vitamin C or vitamin E.24 The study
observed ALA (30 mg/kg body weight daily for two
months) given to diabetic rats either prevented or
significantly attenuated increases in urinary albumin
excretion, fractional albumin clearance, glomerular
volume, and glomerular content of immunoreactive
transforming growth factor-ß and collagen α1 to levels no different from non-diabetic controls. In addition, it was found that ALA, but not vitamins C or
E, significantly increased renal-cortical glutathione
content.
Diabetic Neuropathy
Alpha-lipoic acid has been studied extensively in Europe for the treatment of diabetic neuropathy.25-27 Three large-scale, double-blind, placebocontrolled trials have been conducted on the effect
of ALA for neuropathy – the Alpha-Lipoic Acid in
Diabetic Neuropathy (ALADIN) studies. The first
ALADIN study (n=328 type 2 diabetics) found three
weeks of IV ALA at 600 mg daily was superior to placebo for reducing symptoms of neuropathy.25 ALADIN II examined nerve conduction parameters in a
two-year trial and found improvement in some nerve
conduction parameters with ALA compared to placebo.26 In the seven-month ALADIN III trial, 509 subjects received either 600 mg IV ALA for three weeks,
followed by 600 mg orally three times daily for six
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Alpha-Lipoic Acid
Monograph
months; 600 mg IV ALA daily for three weeks, followed by placebo three times daily for six months;
or double placebo. While no significant differences
were noted in subjective symptom evaluation among
the groups, treatment with ALA was associated with
improvement in nerve function.27
In one randomized, double-blind, placebocontrolled study, known as the SYDNEY trial, 60
type 2 diabetic patients with diabetic sensorimotor
polyneuropathy (DSPN) were administered 600 mg
IV ALA daily, five days/week for a total of 14 treatments, while an equivalent number of DSPN patients
were given placebo for the same duration. At the end
of the trial, the ALA group reported significant improvement in overall symptoms (e.g., lancinating and
burning pain, numbness, and tingling) compared to
the placebo group (average decrease in total symptom score (TSS): 5.7 versus 1.8) (p<0.001).28
Another smaller study demonstrated similar
results using oral ALA. In this trial, 24 type 2 diabetic patients with symptomatic polyneuropathy were
randomly assigned to 600 mg ALA three times daily
or placebo for three weeks. Neuropathic symptoms
(pain, burning, paresthesia, and numbness) in the feet
were scored regularly and summarized as a TSS. At
the end of the trial the ALA group reported significant
improvements in TSS compared to placebo (TSS decreases: 3.8 versus 1.9) (p=0.021).29
Lipid peroxidation is believed to play a role
in the development of neuropathy. In an in vitro study,
lipoic acid decreased lipid peroxidation of nerve tissue.30 ALA significantly reduced neuropathy symptoms in a group of 20 diabetics taking 600 mg daily
for three months. It should be noted that two other
groups of 20 each, receiving vitamin E or selenium,
also experienced significant improvement compared
to the control group.31
ALA may be beneficial for diabetic cardiac
autonomic neuropathy (CAN). A four-month trial of
oral ALA at a dose of 800 mg daily (n=39) or placebo
(n=34) demonstrated a trend toward improvement in
measurements of CAN in the treatment group.32
Cataracts
The enzyme aldose reductase plays an important role in the development of cataracts in diabetes. Lipoic acid inhibited aldose reductase activity
in the rat lens.15 In another animal study, ALA inhibPage 234
ited cataract formation experimentally induced by
buthionine sulfoximine, an inhibitor of glutathione
synthesis. ALA administration maintained levels of
glutathione, ascorbic acid, and alpha-tocopherol in
the lens.33 These same researchers found that R-ALA
reached concentrations in rat lens two- to seven-fold
higher than S-ALA, with the racemic mixture reaching levels between the two.34
Glaucoma
Lipoic acid was administered to 75 subjects
with open-angle glaucoma at dosages of either 75 mg
daily for two months or 150 mg daily for one month.
Thirty-one others served as controls and were given
only local hypotensive therapy. The greatest improvements in the biochemical parameters of glaucoma and
visual function were observed in the group receiving
150 mg lipoic acid.35
Ischemia-Reperfusion Injury
After an area of tissue has been deprived of
blood for a period of time, such as occurs in the brain
after a stroke or in the heart after clot dissolution, reperfusion of the tissues causes a burst of free radical
formation. Several animal studies have demonstrated
the effectiveness of DHLA in the prevention of reperfusion injury.36-40
Animal studies support the efficacy of ALA
as a neuroprotectant after ischemia.41,42 One week after ischemia injury and reperfusion in rats, the amplitude of sensory action potential and sensory conduction velocity was significantly improved with ALA.41
Amanita Mushroom Poisoning
Alpha-lipoic acid infusions were used in
the treatment of amanita mushroom poisoning in 75
patients between 1974 and 1978. Normally, up to
50 percent of patients recover without intervention;
however, 89 percent (67 of 75) recovered after lipoic
acid infusion.43
Alcoholic Liver Disease
Although preliminary studies have indicated
possible benefit of lipoic acid in the treatment of alcoholic liver disease, the only controlled, double-blind
study found ALA had no significant influence on the
course of the disease.44
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Alpha-Lipoic Acid
Monograph
Cognitive Function
Alpha-lipoic acid may have a positive effect
on patients with Alzheimer’s disease and other types
of memory dysfunction secondary to trauma or cerebral vascular accident. By decreasing oxidative damage in the central nervous system, ALA may decrease
the severity of central nervous system disorders.2
An animal study has shown supplementation
with lipoic acid improves long-term memory in aged
mice; however, no effect in young mice was shown.45
This lack of treatment effect in young mice suggests
ALA does not improve memory from a general standpoint; instead, it appears ALA compensates for agerelated memory deficits.
Alpha-lipoic acid also appears to protect brain
cells from the damaging effects of some hazardous
chemicals. Researchers at the University of Rochester
reported neuron damage from excess N-methyl-D-aspartate was prevented by lipoic acid.46 Another study
found buthionine sulfoximine-stimulated neurotoxicity in rat brain was partially prevented by R-ALA, but
not RS-ALA, S-ALA, or RS-DHLA.47
Heavy Metal Toxicity
In vitro and animal studies suggest lipoic
acid supplementation might be a beneficial component in the treatment of heavy metal toxicity, particularly toxicity involving lead, cadmium, mercury, or
copper.2,48-53 In one study an intraperitoneal injection
of 25 mg/kg ALA given to rats for seven days was
able to significantly alter the oxidative stress induced
by lead toxicity.48 Another study demonstrated ALA,
at concentrations of 5 mM, was able to protect rat
hepatocytes from cadmium toxicity (200 µM) by preventing decreases in total glutathione and increases in
lipid peroxidation.49 Furthermore, a study on mercury
intoxication revealed an injection of 10 mg/kg/day
ALA in rats inoculated with 1 mg/kg/day mercuric
chloride prevented damage to nerve tissue caused
by lipid peroxidation.52 Long-Evans Cinnamon rats
have a genetic defect that causes them to accumulate
copper in the liver – in a manner similar to patients
with Wilson’s disease – and spontaneously develop acute hepatitis. ALA has been shown to protect
these rats from developing hepatitis.53 ALA appears
to improve tissue redox status in metal toxicity and
during ­chelation with dithiol compounds, ­including
d­ imercaptosuccinic acid (DMSA).54 Anecdotal reports note the use of lipoic acid may improve the
clearance of toxic metals.
Other Indications
Other therapeutic uses for ALA or DHLA
include protection from radiation injury and prevention of HIV viral replication by inhibition of reverse
transcriptase and nuclear factor kappa-B (a protein
that functions as a nuclear transcription factor and
appears to play a role in inflammation).55,56
Side Effects and Toxicity
Alpha-lipoic acid appears to be safe in dosages generally prescribed clinically. The LD50 was
400-500 mg/kg after an oral dosage in dogs;2 however, lower dosages (20 mg/kg) given intraperitoneally to severely thiamine-deficient rats proved fatal.
These adverse effects were prevented when thiamine
was administered with lipoic acid.57 Anecdotal evidence suggests ALA may be hepatotoxic to cats at
doses greater than 20 mg daily. There have not been
sufficient studies to guarantee safe use in pregnancy.
Allergic skin conditions are among the few reported
side effects of lipoic acid administration in humans.
Dosage
Recommended oral therapeutic dosages of
alpha-lipoic acid range from 600-1800 mg daily. Because R-lipoic acid is more efficiently absorbed and
utilized by the body, R-ALA may be equally effective
at lower doses.
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Alpha-Lipoic Acid
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